The invention relates to lipid/polymer-containing biodegradable pharmaceutical compositions which are designed to provide controlled release of encapsulated physiologically active substances.
Delivery systems offer the advantage of improved bioavailability and a higher therapeutic index over a prolonged period of time for physiologically active substances. Two major classes of drug-delivery systems are formed from either biodegradable polymers or lipids (Langer, R., Nature 392: 5-10, 1998). Polymer-based drug-delivery systems have been developed as microspheres for injection, implants, transdermal patches, and aerosols for inhalation (Domb et al., Handbook of Biodegradable Polymers, Harwood Academic Publishers, Amsterdam, 1997; Putney et al., Nature Biotechnology 16: 153-157, 1998; Edwards et al., Science 276: 1868-1871, 1997). Lipid-based drug delivery systems have been developed as unilamellar, multilamellar (Gregoriadis, Liposome Technology, Vols. I, II, III, CRC Press, Boca Raton, Fla., 1993) and multivesicular liposomes (U.S. Pat. No. 5,422,120 to Kim; U.S. Pat. No. 5,723,147 to Kim et al.; U.S. Pat. No. 5,767,627 to Sankaram et al.; U.S. patent application Ser. No. 08/305,158; U.S. patent application Ser. Nos. 08/723,583, 08/925,532, 08/792,566, and 08/925,531).
One of the limitations of using biodegradable polymers is that pharmaceutical compositions such as microspheres prepared from biodegradable polymers require storage under anhydrous conditions due to their susceptibility to hydrolysis. As a result, a typical pharmaceutical package of microspheres for injection consists of one vial with an anhydrous formulation of a biodegradable polymer and a physiologically active substance as a solid dosage form and another vial with an aqueous reconstitution medium (e.g., Lupron Depot, Physicians Desk Reference, pp. 2739-2746, Medical Economics Company, Inc., Montvale, N.J., 1997). The contents of the two vials are mixed immediately prior to injection.
Microspheres are prepared by a single emulsification process (U.S. Pat. No. 4,389,330 to Tice et al.; U.S. Pat. No. 3,691,090 to Kitajima et al.), a double emulsification process (Edwards et al., Science 276: 1868-1871, 1997), a phase inversion microencapsulation process (Mathiowitz et al., Nature 386: 410-413, 1997), or an atomization-freeze process (Putney and Burke, Nature Biotechnology 16: 153-157, 1998). In the single emulsification process, a volatile organic solvent phase containing a biodegradable polymer, an aqueous solution necessarily containing an emulsifier such as polyvinyl alcohol, and a physiologically active substance are homogenized to produce an emulsion. The solvent is evaporated and the resulting hardened microspheres are freeze-dried.
In the double emulsification process, an aqueous solution which may contain a physiologically active substance and an volatile organic solvent phase containing a biodegradable polymer are homogenized to form an emulsion. The emulsion is mixed with another aqueous solution, which contains an emulsifier such as polyvinyl alcohol. Evaporation of the solvent and freeze-drying produces microspheres.
In the phase inversion microencapsulation process, drug is added to a dilute polymer solution in a solvent (e.g. dichloromethane) which is then poured rapidly into an unstirred bath of another liquid (e.g. petroleum ether) causing nano- and microspheres to form spontaneously. In the atomization-freeze process, micronized solid physiologically active substance is suspended in a solvent phase containing a biodegradable polymer that is then atomized using sonication or air-atomization. This produces droplets that are then frozen in liquid nitrogen. Addition of another solvent in which both the polymer and the drug are insoluble extracts the solvent from the microspheres.
Microspheres prepared by the single-emulsification process or the double-emulsification process methods can be aerosolized (Edwards et al., Science 276: 1868-1871, 1997). Addition of dipalmitoyl phosphatidylcholine to the solvent phase increases particle size, porosity, and efficiency of aerosolization and decreases the mass density. However, formation of the large porous particles still requires an emulsifier such as polyvinyl alcohol. Sucrose stearate, magnesium stearate, aluminum tristearate, sorbitan fatty esters, and polyoxyethylene fatty ethers have been used as droplet stabilizers in a solvent evaporation method for producing microspheres from acrylic polymers (Yuksel et al., J. Microencapsulation 14: 725-733, 1997). Poloxamer 188, or Pluronic F68, has been used as a nonionic surfactant in the primary emulsion, in addition to polyvinyl alcohol in the second aqueous phase, for producing microspheres from poly(lactide) using a double emulsification process (Nihant et al., Pharm. Res. 11: 1479-1484, 1994). The hydrophilic additives, 2-hydroxypropyl xcex2-cyclodextrin, methyl xcex2-cyclodextrin, Pluronic F-127, L-tartaric acid dimethyl ester, and a hydrophobic additive, beeswax (which consists of esters of long-chain monohydric alcohols with even-numbered carbon chains, esterified with long-chain acids, also having even numbers of carbon atoms) were used to produce poly(lactide-glycolide) double-layer films (Song et al., J. Controlled Rel. 45: 177-192, 1997).
The invention is based on the discovery that biodegradable microspheres can be produced which include both polymer and lipid components, and are free of surfactants introduced into a second aqueous phase of the microspheres. A typical surfactant which heretofore had been introduced into the second aqueous phase is polyvinyl alcohol. Production of the biodegradable microspheres of the invention involves substantial or complete removal of volatile organic solvent from the microsphere walls. The microspheres can be loaded with physiologically active substances, which are released in vitro and in vivo. The rate of release can be easily controlled by adjustments of the lipid/polymer ratio. Previously available microsphere compositions required a change in the identity of the polymer.
In one aspect, the invention provides a lipid/polymer-containing pharmaceutical composition including a biodegradable microsphere which includes at least one type of biodegradable polymer which is soluble in organic solvents, and at least one type of lipid. Also included in the composition is a physiologically active substance which is releasable from the biodegradable microsphere. The composition is preferably substantially free of volatile organic solvent, and most preferably substantially free of polyvinyl alcohol. The compositions can be in the form of an aqueous suspension, or alternatively in the form of a solid dosage, such as in the tablet, capsule, wafer, transdermal patch, suture, implant, or suppository form.
The biodegradable polymers can be homopolymers such as polylactides, polyglycolides, poly(p-dioxanones), polycaprolactones, polyhydroxyalkanoates, polypropylenefumarates, polyorthoesters, polyphosphate esters, polyanhydrides, polyphosphazenes, polyalkylcyanoacrylates, polypeptides, or genetically engineered polymers. At the same time, the biodegradable polymers can be copolymers (random or block) such as poly(lactide-glycolides), poly(p-dioxanone-lactides), poly(p-dioxanone-glycolides), poly(p-dioxanone lactide-glycolides), poly(p-dioxanone-caprolactones), poly(p-dioxanone-alkylene carbonates), poly(p-dioxanone-alkylene oxides), poly(p-dioxanone-carbonate-glycolides), poly(p-dioxanone-carbonates), poly(caprolactone-lactides), poly(caprolactone-glycolides), poly(hydroxyalkanoates), poly(propylenefumarates), poly(orthoesters), poly(ether-esters), poly(ester-amides), poly(ester-urethanes), polyphosphate esters, polyanhydrides, poly(ester-anhydrides), polyphosphazenes, polypeptides and genetically engineered copolymers. The lipids of the pharmaceutical compositions can be zwitterionic lipids, acidic lipids, cationic lipids, sterols, or triglycerides of many types, including many phospholipids.
The physiologically active substances can be hydrophilic, in which case the compositions desirably also include a triglyceride, or they can be hydrophobic, in which case the composition can be substantially free of triglycerides, or they can be amphipathic. The physiologically active substances can be generally classified as antianginas, antiarrhythmics, antiasthmatic agents, antibiotics, antidiabetics, antifingals, antihistamines, antihypertensives, antiparasitics, antineoplastics, antivirals, cardiac glycosides, cytokines such as erythropoietin, herbicides, hormones, immunomodulators, monoclonal antibodies, neurotransmitters, nucleic acids, proteins, radio contrast agents, radionuclides, sedatives, analgesics, steroids, tranquilizers, vaccines, vasopressors, anesthetics, peptides, and combinations thereof.
In another aspect, the invention provides a way to vary the rate of release of physiologically active substances by varying the lipid to polymer ratio in the compositions of the invention.
In yet another aspect, the invention provides a method for producing biodegradable lipid/polymer compositions of the invention, including a) forming a water-in-oil type emulsion, which includes a first aqueous phase and a volatile organic phase, b) dispersing the emulsion in a second aqueous phase to form solvent spherules, and c) removing the volatile organic solvent to form the lipid/polymer-containing compositions. A pharmaceutically active substance can be included in the process of making the water-in-oil type emulsion, to produce a pharmaceutical composition. The organic solvent is preferably substantially completely removed.
In a further aspect of the invention, pharmaceutical compositions produced by the above process are provided. If the process involves the use of a hydrophilic pharmaceutically active substance, the process further includes a triglyceride in the process of making the water-in-oil type emulsion.
In a further aspect, the invention provides a method of treating a patient with the pharmaceutical compositions of the invention.
One objective of the present invention is to provide a novel pharmaceutical composition as a drug-delivery system with a physiologically active substance encapsulated within, the composition enabling release of the substance over a prolonged period of time. Another objective is to provide a means of controlling the rate of release of the substance from the composition. Another objective is to provide a means of storing the composition either as a solid dosage form or a semi-solid dosage form.
Preparation of microspheres from biodegradable polymers according to the prior art requires that polyvinyl alcohol be used in the second aqueous solution of a double emulsification process. When an emulsifier such as polyvinyl alcohol is not included in the second aqueous phase of a double emulsion process, the physiologically active substance cannot be encapsulated in prior art microspheres. The compositions of the present invention do not use polyvinyl alcohol in the second aqueous solution. Polyvinyl alcohol is also not utilized in any other aqueous solution for the pharmaceutical compositions of the present invention. In addition to polyvinyl alcohol, the present compositions do not include sucrose stearate, magnesium stearate, aluminum tristearate, sorbitan fatty esters, polyoxyethylene fatty ethers, Poloxamer 188, Pluronic F68, 2-hydroxypropyl xcex2-cyclodextrin, methyl xcex2-cyclodextrin, Pluronic F-127, or L-tartaric acid dimethyl ester.
Rather, the volatile organic solvent phase contains a mixture of lipids and biodegradable polymer. Higher yield and a greater loading of the physiologically active substance are obtained for the lipid/polymer-containing pharmaceutical compositions of the present invention than for polymer microspheres of the prior art.
A variety of physiologically active substances can be encapsulated into the pharmaceutical compositions of the present invention. The useful substances include small molecules, peptides, proteins and nucleic acids. A variety of biodegradable polymers with different lactide:glycolide ratios and different molecular weights can be used for preparing the pharmaceutical compositions of the present invention.
The lipid composition can be varied in order to optimize yield and loading of the physiologically active substance. Thus, there is no requirement of changing the identity of the polymer to affect the loading, yield or release rate of the physiologically active substances to be released. For hydrophobic physiologically active substances, excellent yields and loading are obtained when the pharmaceutical composition does not contain a triglyceride. For hydrophilic physiologically active substances, yield and loading are excellent when the pharmaceutical composition contains a triglyceride.
The pharmaceutical compositions of the present invention afford release of the physiologically active substance into physiological fluids in vitro over a sustained period. Encapsulated physiologically active substances are released into human plasma with sustained release characteristics under two different assay conditions. Varying the lipid:polymer ratio in the pharmaceutical composition can control the rate of release of the physiologically active substance. Controlling the release rate allows one to ensure that the concentration of physiologically active substance is constantly within the therapeutic window; that is, within a concentration range that is high enough to be efficacious, but not so high as to be toxic.
The pharmaceutical compositions of the present invention also afford release of the physiologically active substance in viva over a sustained period. Serum concentrations of physiologically active substances determined at various times after administration in the unencapsulated form, encapsulation in a lipid-only composition, encapsulation in a polymer-only composition, and encapsulation in a lipid/polymer-containing composition of the present invention show that the serum concentration of physiologically active substances peaked at a later time, and was higher for the inventive pharmaceutical compositions than that observed for the other three compositions. Alternately, those encapsulated physiologically active substances which inhibit the release of endogenous serum components (for example, hormones, enzymes, proteins, carbohydrates and the like) show a decrease in the serum concentration of the inhibited component which was longer lasting than that observed for unencapsulated physiologically active substance.
Microsphere compositions prepared from biodegradable polymers according to the prior art are not suitable for storage in aqueous media since the polymer degrades rapidly upon exposure to hydrous conditions. However, the polymer in the lipid/polymer-containing compositions of the present invention is protected against hydrolysis both in accelerated stability studies with heat and acid stress and under normal storage conditions.
The term xe2x80x9csolvent spherulexe2x80x9d as used throughout the specification and claims means a microscopic spheroid droplet of organic solvent, within which are multiple smaller droplets of a first aqueous solution. The solvent spherules are suspended and totally immersed in a second aqueous solution. The term xe2x80x9creleasable from biodegradable microspheresxe2x80x9d refers to the condition that upon sufficient biodegradation of the microspheres, the physiologically active substance (encapsulated within the microsphere) is able to exert its physiological effect. Implicit in the definition is the idea that when the substance is not released, its effect is diminished to the extent that a physiological effect is not observable. The physiologically active substances can be released from not only the interior of a microsphere, but also from the microsphere wall (matrix). If the physiologically active substance is attached or appended to the matrix, physical separation of the microsphere and matrix is not required for xe2x80x9crelease from the biodegradable microspherexe2x80x9d. The term xe2x80x9ctherapeutically effectivexe2x80x9d as it pertains to the compositions of this invention, means that a physiologically active substance present in the microspheres is released in a manner sufficient to achieve a particular level of treatment of a disorder.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.